(a) Field of the Invention
This invention relates to octahydropyrido[1,2-c]pyrimidinones and hexahydropyrido[1,2-c]pyrimidinediones that are useful as inhibitors of cardiac arrhythmias and are therefore useful in the treatment of irregular heartbeat.
Arrhythmias are disorders relating to electrical impulse generation in the heart. The disorders include premature contractions (extrasystoles) originating in abnormal or ectopic foci in atria or ventricles; atrial flutter; atrial fibrillation; and ventricular tachycardia and fibrillation. For a discussion on these disorders, see, for example, L. S. Goodman and A. Gilman, eds., The Pharmacological Basis of Therapeutics, Sixth Edition; New York: Macmillan Publishing Co., 1980; pp. 761-767.
A number of compounds have been developed to alter cardiovascular function related to heart rate and rhythm. See Goodman and Gilman, pp. 730-731, 750-751, 768-786. The cardiac glycosides, including digitalis, have as their main pharmacodynamic property the ability to increase the force of myocardial contraction. This positive inotropic action is the basis of the salutary effects of these cardiac glycosides in congestive heart failure--increased cardiac output; decreased heart size, venous pressure, and blood volume; and diuresis and relief of edema. Quinidine is useful in the therapy of atrial fibrillation but exhibits several toxic reactions, such as cinchonism. Procainamide acts in essentially the same manner as quinidine, and also exhibits toxic side effects. Lidocaine, a widely used local anesthetic, may be used in the treatment of ventricular arrhythmias, but must be administered by injection. Propranolol is useful in the treatment of supraventricular tachycardias and ventricular arrhythmias, but must be used with great care because it may induce significant hypotension, left ventricular failure, or even cardiovascular collapse. Disopyramide has effects somewhat like procainamide and quinidine, all being so-called Type 1 antiarrhythmics. At therapeutic levels disopyramide shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the refractory period of the A-V node. However, because of the anticholinergic effects of some of the Type 1 antiarrhythmics, such as disopyramide, they should not be used in patients with glaucoma, myasthenia gravis, or problems of urinary retention.
(b) Prior Art
As previously described, a number of compounds are useful in the treatment of cardiac arrhythmia. U.S. Pat. No. 4,560,754 discloses certain antiarrhythmic 1,3-diazabicyclo[4.4.0]decan-4-ones and 1,3-diazabicyclo[4.4.0]dec-2-en-4-ones, including compounds of the following general structure: ##STR1## wherein R.sub.1 may be hydrogen, lower alkyl, or optionally substituted phenyl; R.sub.2 and R.sub.3 are lower alkyl; R.sub.4 may be hydrogen, but only if the ring nitrogen is not involved in double bonding; and X may be any of several substituents. Thus, in contrast to the present invention, U.S. Pat. No. '754 does not disclose compounds in which R.sub.1 is OH, .dbd.O, NH.sub.2, or .dbd.NH nor compounds in which R.sub.4 may be any substituent other than hydrogen.
In addition, U.S. Pat. No. 4,567,270 discloses certain hexahydroindolizinones (or 1-azabicyclo[4.3.0]nonan-9-ones). In contrast to the compounds of the present invention, the hexahydroindolizinones of Ser. No. '210 are characterized by a bicyclic skeleton of fused five- and six-membered rings containing a single ring nitrogen at a bridgehead position and bear substituents around the rings at distinctly different locations.